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A role for leukocyte-endothelial adhesion mechanisms in epilepsy

Abstract

The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1,2,3. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins α4β1 and αLβ2. Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.

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Figure 1: α4 integrin, VCAM-1 and PSGL-1 dependence of PMN and TH1 cell interactions with brain endothelium after status epilepticus.
Figure 2: Effect of blockade or deficiency in leukocyte adhesion mechanisms on convulsions and seizures.
Figure 3: Effect of blockade or deficiency in leukocyte adhesion mechanisms on CNS structure and neuronal density.
Figure 4: Inhibition or deficiency of leukocyte adhesion pathways maintains the integrity of the BBB.

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Acknowledgements

Antibody to PSGL-1 (4RA10) was kindly provided by D. Vestweber, Max Plank Institute. We wish to thank C. Laudanna for critically discussing the manuscript. This work was supported in part by grants from the Fondazione Cariverona, Ministero dell'Università e della Ricerca (MIUR)–Progetti di ricerca di interese nazionale, the US National Multiple Sclerosis Society, Fondo Incentivazione Ricerca di Base, the Italian Ministry of Health; Fondazione Italiana Sclerosi Multipla, the University of Verona ex 60% MIUR (to G.C.); the European Community Research Grants LSH-CT-2006-037315 (EPICURE, thematic priority LIFESCIHEALTH; University of Verona ex 60% MIUR (to P.F.F.); and by US National Institutes of Health grants (to E.C.B., L.X., R.P.M. and J.B.L.). L.O. was supported in part by a fellowship from Fondazione Italiana Sclerosi Multipla. The authors are grateful to S. Fiorini, I. Cwojdzinski, P. Bernardi, M. Pellitteri, S. Becchi, L. Andrello and A. Calbi for their invaluable help in the experimental procedures.

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Authors and Affiliations

Authors

Contributions

G.N.M., D.B., A.C., L.Z. and F.S. performed epilepsy experiments, telemetry and open field behavior. M.M., B.R., L.O., S.B. and S.A. performed intravital microscopy, in vivo staining for adhesion molecules, adhesion assays and contributed to obtaining the behavioral data. A.O. provided the human samples. F.M., A.C. and F.O. performed immunohistochemistry on human and animal samples. P.M., E.N. and A.S. provided MRI expertise. J.W.H., L.X., J.B.L. and R.P.M. provided key reagents and mice. E.C.B. contributed experimental suggestions, reagents and assistance with writing. P.F.F. and G.C. designed the study, analyzed the data and wrote the paper.

Corresponding authors

Correspondence to Paolo F Fabene or Gabriela Constantin.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4, Supplementary Tables 1–3, Supplementary Methods and Supplementary Discussion (PDF 587 kb)

Supplementary Video 1

This movie shows SE-induction in WT mice after pilocarpine administration paralleled by the normal behavior of mice lacking fucosyltransferase (FucT)-VII activity (MOV 2391 kb)

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Fabene, P., Mora, G., Martinello, M. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14, 1377–1383 (2008). https://doi.org/10.1038/nm.1878

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